A new study in the Journal of the American Medical Association examined 188 new drugs that were approved by the FDA between 2005 and 2012 for 206 indications on the basis of 448 pivotal efficacy trials, but found that one-third of the indications were approved on the basis of just a single trial.

Ed Silverman, Forbes, Jan 21, 2014

As the FDA seeks to approve drugs not only more quickly but also accommodate a growing clamor to exhibit more flexibility for endorsing therapies for life-threatening diseases, a curious wrinkle has emerged - there is a wide variation in the quality of underlying evidence used for approvals.

A new study in the Journal of the American Medical Association examined 188 new drugs that were approved by the FDA between 2005 and 2012 for 206 indications on the basis of 448 pivotal efficacy trials, but found that one-third of the indications were approved on the basis of just a single trial. And trials using surrogate endpoints as a primary outcome were the only basis of approval for 91 indications.

What’s more, the trial features differed by choice of comparators and endpoints, duration, patient size studied and completion rates. The upshot is that, while the FDA needs to remain flexible, the trial designs and subsequent approvals suggest that these drugs may require added scrutiny once they are in the marketplace.

“Flexible approval standards may lead to some therapeutics agents being approved by the FDA on the basis of numerous rigorously designed clinical trials and others on the basis of fewer or less robust studies, leading to differing levels of certainty about the risks and benefits of newly approved drugs,” the researchers write.

Of course, the FDA attempts to be flexible given the need to consider treatments for which no effective options exist, a reality that has led to various approaches used to hasten medicines to market, notably accelerated approvals, breakthrough therapy designations and an increasing reliance on surrogate markers, in some cases.

Recently released FDA data show that, of 27 new molecular entities approved last year, two were accelerated. Meanwhile, 10 were granted fast track status since they answered unmet medical needs; 10 were given priority review in hopes of significantly advancing medical care and three of these two groups were also designated as breakthroughs because they demonstrated substantial improvement on at least one clinically significant endpoint over available therapies (more here).

And as the JAMA researchers note, faster approvals can be made without requiring costly and time-consuming, randomized, double-blinded clinical trials, even though these are widely considered to be the “gold standard” in drug research. This is especially true for various forms of cancer.

In fact, the JAMA study found that 89 percent of the trials examined were randomized and nearly 80 percent were double-blinded. More than used a placebo for comparison and 32 percent compared different medicines, although 13 percent lacked such a comparison (here is the study).

Just the same, the researchers express caution. “We’re not implying that the FDA did not do a good job of evaluating drugs or making a thorough investigation of safety and efficacy,” says Joseph Ross, an assistant professor of medicine and public health at the Yale University School of Medicine.

“But there is an assumption among patients and physicians that drugs are safe and work, and there’s more uncertainty than meets the eye. We think the data show we may not know as much as we think we know and some of these medicines deserve much more scrutiny in the post-marketing period.”

“Yes, certain drugs have been demonstrated to work in short studies often focused on surrogate endpoints, but how much do we really know going forward? The assumption is worth taking a good look at. I’m not sure every therapy given accelerated approval or breakthrough designation is necessary.

“This is a core issue the FDA wrestles with - getting products to market quickly and balancing that against public health. I sympathize with the agency, which has managed this difficult problem, but if they’re going to make decisions based on single trials without being validated in a second population, well, that’s an issue. It’s a core tenet of science to replicate in a larger trial in a follow-up period.”

Of course, such sentiments may cause concern among drug makers, physicians and patient advocacy groups that, understandably, want to see the FDA continue to work harder to find ways to approve drugs more quickly. But the issue is not really black and white, and a more nuanced approach is warranted, especially as more medicines do reach the marketplace at a faster clip than ever before.